Throughout this application, various publications are referenced to in full citations. The disclosures of these publications are hereby incorporated by reference into this application to describe more fully the state of the art to which this invention pertains.
The cyclic nucleotides, cyclic-adenosine monophosphate (cAMP) and cyclic-guanosine monophosphate (cGMP) function as intracellular second messengers regulating a vast array of processes in neurons. Intracellular cAMP and cGMP are generated by adenyl and guanyl cyclases, and are degraded by cyclic nucleotide phosphodiesterases (PDEs). Intracelluar levels of cAMP and cGMP are controlled by intracellular signaling, and stimulation/repression of adenyl and guanyl cyclases in response to GPCR activation is a well characterized way of controlling cyclic nucleotide concentrations (Antoni, F. A. Front. Neuroendocrinol. 2000, 21(2), 103-132). In neurons, this includes the activation of cAMP and cGMP dependent kinases and subsequent phosphorylation of proteins involved in acute regulation of synaptic transmission as well as in neuronal differentiation and survival.
There are 21 phosphodiesterase genes that can be divided into 11 gene families. There are ten families of adenylyl cyclases, two of guanylyl cyclases, and eleven of phosphodiesterases. PDEs are a class of intracellular enzymes that regulate levels of cAMP and cGMP via hydrolysis of the cyclic nucleotide into their respective nucleotide monophosphates. Some PDEs degrade cAMP, some cGMP and some both. Most PDEs have a relatively widespread expression and have roles in many tissues, while some are more spatially restricted.
Phosphodieasterase 10A (PDE10A) is a dual specificity phosphodiesterase that can convert both cAMP to AMP and cGMP to GMP (Loughney, K. et al. Gene 1999, 234, 109-117; Fujishige, K. et al. Eur. J. Biochem. 1999, 266, 1118-1127 and Soderling, S. et al. Proc. Natl. Acad. Sci. 1999, 96, 7071-7076). PDE10A is primarily expressed in the neurons in the striatum, n. accumbens and in the olfactory tubercle (Kotera, J. et al. Biochem. Biophys. Res. Comm. 1999, 261, 551-557 and Seeger, T. F. et al. Brain Research, 2003, 985, 113-126).
Mouse PDE10A is the first member of the PDE10 family of phosphodiesterases (Fujishige, K. et al. J. Biol. Chem. 1999, 274, 18438-18445 and Loughney, K. et al. Gene 1999, 234, 109-117) and N-terminal splice variants of both the rat and human genes have been identified (Kotera, J. et al. Biochem. Biophys. Res. Comm. 1999, 261, 551-557 and Fujishige, K. et al. Eur. J. Biochem. 1999, 266, 1118-1127). There is a high degree of homology across species. PDE10A is uniquely localized in mammals relative to other PDE families. mRNA for PDE10 is highly expressed in testis and brain (Fujishige, K. et al. Eur J. Biochem. 1999, 266, 1118-1127; Soderling, S. et al. Proc. Natl. Acad. Sci. 1999, 96, 7071-7076 and Loughney, K. et al. Gene 1999, 234, 100-117). These studies indicate that within the brain, PDE10 expression is highest in the striatum (caudate and putamen), n. accumbens and olfactory tubercle. More recently, an analysis has been made of the expression pattern in rodent brain of PDE10A mRNA (Seeger, T. F. et al. Abst. Soc. Neurosci. 2000, 26, 345.10) and PDE10A protein (Menniti, F. S. et al. William Harvey Research Conference ‘Phosphodiesterase in Health and Disease’, Porto, Portugal, Dec. 5-7, 2001).
PDE10A is expressed at high levels by the medium spiny neurons (MSN) of the caudate n., n. accumbens and the corresponding neurons of the olfactory tubercle. This constitutes the core of the basal ganglia system. The MSN make up a role in a cortical-basal ganglia-thalamocortical loop, integrating convergent cortical/thalamic input, and sending this integrated information back to the cortex. Furthermore, MSN express two functional classes of neurons: the D1 class expressing D1 dopamine receptors and the D2 class expressing D2 dopamine receptors. The D1 class of neurons is part of the ‘direct’ striatal output pathway, which broadly functions to facilitate behavioral responses. The D2 class of neurons is part of the ‘indirect’ striatal output pathway, which functions to suppress behavioral responses that compete with those being facilitated by the ‘direct’ pathway. These competing pathways act like the brake and accelerator in a car. In the simplest view, the poverty of movement in Parkinson's disease results from over-activity of the ‘indirect’ pathway, whereas excess movement in disorders such as Huntington's disease represent over-activity of the direct pathway. PDE10A regulation of cAMP and/or cGMP signaling in the dendritic compartment of these neurons may be involved in filtering the cortico/thalamic input into the MSN. Furthermore, PDE10A may be involved in the regulation of GABA release in the substantia nigra and globus pallidus (Seeger, T. F. et al. Brain Research, 2003, 985, 113-126).
Dopamine D2 receptor antagonism is well established in the treatment of schizophrenia. Since the 1950's, dopamine D2 receptor antagonism has been the mainstay in psychosis treatment and all effective antipsychotic drugs antagonise D2 receptors. The effects of D2 are likely to be mediated primarily through neurons in the striatum, n. accumbens and olfactory tubercle, since these areas receive the densest dopaminergic projections and have the strongest expression of D2 receptors (Konradi, C. and Heckers, S. Society of Biological Psychiatry, 2001, 50, 729-742). Dopamine D2 receptor agonism leads to decrease in cAMP levels in the cells where it is expressed through adenylate cyclase inhibition, and this is a component of D2 signalling (Stoof, J. C. and Kebabian J. W. Nature 1981, 294, 366-368 and Neve, K. A. at al. Journal of Receptors and Signal Transduction 2004, 24(3), 165-205). Conversely, D2 receptor antagonism effectively increases cAMP levels, and this effect could be mimicked by inhibition of cAMP degrading phosphodiesterases.
Most of the 21 phosphodiesterase genes are widely expressed; therefore inhibition is likely to have side effects. Because PDE10A, in this context, has the desired expression profile with high and relatively specific expression in neurons in striatum, n. accumbens and olfactory tubercle, PDE10A inhibition is likely to have effects similar to D2 receptor antagonism and therefore have antipsychotic effects.
While PDE10A inhibition is expected to mimic D2 receptor antagonism in part, it might be expected to have a different profile. The D2 receptor has signalling components besides cAMP (Neve, K. A. et al. Journal of Receptors and Signal Transduction 2004, 24(3), 165-205), wherefore interference with cAMP through PDE10A inhibition may negatively modulate rather than directly antagonise dopamine signaling through D2 receptors. This may reduce the risk of the extrapyrimidal side effects that are seen with strong D2 antagonism. Conversely, PDE10A inhibition may have some effects not seen with D2 receptor antagonism. PDE10A is also expressed in D1 receptors expressing striatal neurons (Seeger, T. F. et al. Brain Research, 2003, 985, 113-126). Since D1 receptor agonism leads to stimulation of adenylate cyclase and resulting increase in cAMP levels, PDE10A inhibition is likely to also have effects that mimic D1 receptor agonism. Finally, PDE10A inhibition will not only increase cAMP in cells, but might also be expected to increase cGMP levels, since PDE10A is a dual specificity phosphodiesterase. cGMP activates a number of target protein in cells like cAMP and also interacts with the cAMP signalling pathways. In conclusion, PDE10A inhibition is likely to mimic D2 receptor antagonism in part and therefore has antipsychotic effect, but the profile might differ from that observed with classical D2 receptor antagonists.
The PDE10A inhibitor papaverin is shown to be active in several antipsychotic models. Papaverin potentiated the cataleptic effect of the D2 receptor antagonist haloperidol in rats, but did not cause catalepsy on its own (WO 03/093499). Papaverin reduced hyperactivity in rats induced by PCP, while reduction of amphetamine induced hyperactivity was insignificant (WO 03/093499). These models suggest that PDE10A inhibition has the classic antipsychotic potential that would be expected from theoretical considerations. WO 03/093499 further discloses the use of selective PDE10 inhibitors for the treatment of associated neurologic and psychiatric disorders. Furthermore, PDE10A inhibition reverses subchronic PCP-induced deficits in attentional set-shifting in rats (Rodefer, et al. Eur. J. Neurosci. 2005, 4, 1070-1076). This model suggests that PDE10A inhibition might alleviate cognitive deficits associated with schizophrenia.
Accordingly, signal enhancement via elevation of cAMP and cGMP can be induced through the administration of PDE10A inhibitors to treat associated neurological and psychiatric disorders. The PDE10A inhibitors of the present invention are expected to serve as therapies for the treatment of associated neurological and psychiatric disorders and may have the benefit of not possessing unwanted side effects, which are associated with the current therapies on the market.
Furthermore, recent publications (WO 2005/120514, WO 2005012485, Cantin et al, Bioorganic & Medicinal Chemistry Letters 17 (2007) 2869-2873) suggest that PDE10A inhibitors may be useful for treatment of obesity and non-insulin dependent diabetes.
With respect to inhibitors of PDE10A, EP 1250923 discloses the use of selective PDE10 inhibitors in general, and papaverine in particular, for the treatment of certain neurologic and psychiatric disorders.
WO 05/113517 discloses benzodiazepine stereospecific compounds as inhibitors of phosphodiesterase, especially types 2 and 4, and the prevention and treatment of pathologies involving a central and/or peripheral disorder. WO 02/88096 discloses benzodiazepine derivatives and their uses as inhibitors of phosphodiesterase, especially type 4 in the therapeutic field. WO 04/41258 discloses benzodiazepinone derivatives and their uses as inhibitors of phosphodiesterase, especially type 2 in the therapeutic field.
Pyrrolodihydroisoquinolines and variants thereof are disclosed as inhibitors of PDE10 in WO 05/03129 and WO 05/02579. Piperidinyl-substituted quinazolines and isoquinolines that serve as PDE10 inhibitors are disclosed in WO 05/82883. WO 06/11040 discloses substituted quinazoline and isoquinoline compounds that serve as inhibitors of PDE10. US20050182079 discloses substituted tetrahydroisoquinolinyl derivatives of quinazoline and isoquinoline that serve as effective phosphodiesterase (PDE) inhibitors. In particular, US20050182079 relates to said compounds, which are selective inhibitors of PDE-10. Analogously, US20060019975 discloses piperidine derivatives of quinazoline and isoquinoline that serve as effective phosphodiesterase (PDE) inhibitors. US20060019975 also relates to compounds that are selective inhibitors of PDE10.
WO 06/028957 discloses cinnoline derivatives as inhibitors of phosphodiesterase type 10 for the treatment of psychiatric and neurological syndromes.
However, these disclosures do not pertain to compounds comprising cyanoisoquinoline attached to 2-arylpiperazine, 2-arylthiomorpholine or 2-arylmorpholine via a N—C linkage; said compounds having now been found by the inventors to be highly active PDE10A enzyme inhibitors. Such compounds may offer alternatives to current marketed treatments for neurodegenerative and/or psychiatric disorders, which are not efficacious in all patients. Hence, there remains the need for alternative methods of treatment.
The Phosphodiesterase 3 (PDE3) family consists of two genes PDE3A and PDE3B. They encode enzymes that can hydrolyse cAMP and cGMP to AMP and GMP, respectively. PDE3A is relatively highly expressed in platelets, vascular smooth muscle, cardiac myocytes, and oocytes. PDE3B is a major PDE in adipose tissue, liver, pancreas, as well as in cardiovascular tissues. PDE3 inhibitors have been approved for treatment of congestive heart failure. However, while they are beneficial in acute treatment, chronic treatment with PDE3 inhibitors resulted in a significant increase in mortality (Matthew A. Movsesian, Journal of Cardiac Failure Vol. 9 No. 6, 2003, 475-480).
Several PDE10 inhibitors containing the 6,7-dimethoxy-quinazoline motif have been described previously (Chappie et al.: Discovery of a Series of 6,7-Dimethoxy-4-pyrrolidylquinazoline PDE10A Inhibitors, American Chemical Society, Published on Web Dec. 22, 2006). The 6,7-dimethoxy-quinazoline containing compounds described herein all exhibited significant PDE3 activity—all had PDE3A IC50's of less than 800 nM. Thus, achieving selectivity towards PDE3 appears to be a common problem for PDE10 inhibitors with this motif that poses a serious problem for their potential use in chronic treatment given the propensity of pde3 inhibition to cause cardiac side effects.